5-(arloxymethyl)oxazolines

ABSTRACT

The invention relates to compounds of formula (I): ##STR1## wherein: R 1  and R 2  are selected, each independently of the other, from hydrogen and an alkyl radical, 
     A is selected from the radicals: ##STR2## wherein: R 3  represents a radical selected from halogen, alkyl, alkoxy, amino, 2-acetyl, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, trifluoromethyl and cyano, 
     R 4 , R 5 , R 6 , R 7  and R 8  are selected, each independently of the others, from hydrogen, a halogen, an alkyl, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, cyano and a trifluoromethyl radical, 
     R 9  represents the nitro radical, 
     with the proviso that A cannot represent a grouping selected from: dihalophenyl, trihalophenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tert-butylphenyl and 3-(dimethylamino)phenyl, 
     optical isomers thereof in pure form or in the form of a mixture, and pharmaceutically acceptable addition salts thereof with an acid or base, 
     it being understood that: the terms &#34;alkyl&#34; and &#34;alkoxy&#34; represent straight-chained or branched radicals having from 1 to 6 carbon atoms. The compounds of the invention and the pharmaceutical compositions comprising them are proving to be useful in the treatment of disorders associated with I 1  -receptors.

The invention relates to new 5-(aryloxymethyl)oxazolines, a process forthe preparation thereof and pharmaceutical compositions containing them.

5- (2,4,6-trihalophenoxy)methyl!-2-oxazolines (U.S. Pat. No. 3,818,028),which are described as anti-depressants, and 5-(3,4-dihalophenoxy)methyl!-2-oxazolines (U.S. Pat. No. 3,637,726), whichare described as anti-microbial agents, are known from the literature.

The publication by C. Jarry et al (Eur. J. Med. Chem., 25(4), (1990),379-382) presents phenoxymethyloxazolines that are used as startingmaterials in the synthesis of phenacylimino-oxazolidines.

5-(phenylphenoxymethyl)-2-oxazolines that have anti-depressantproperties have also been described in patent specification EP-A-392929.

Finally, C. Jarry et al (Bull. Soc. Pharm. Bordeaux, (1981), 120,153-162) have demonstrated the anti-hypertensive properties of certain2-amino-2-oxazolines. Those compounds, however, have, in addition, astimulant action of central origin.

The object of the present invention is to find new compounds that haveanti-hypertensive properties and do not have secondary effects ofcentral origin.

Thus, the present invention relates to new 5-(aryloxymethyl)oxazolineshaving a strong affinity for the imidazoline I₁ -receptors (I₁-receptor).

Surprisingly, that affinity is selective, since the compounds of theinvention do not have comparable affinity for the imidazoline I₂-receptors (I₂ -receptors) or for the α₁ - and α₂ -adrenoreceptors whichare responsible for the secondary effects of central origin.

As a result, the compounds of the invention will advantageously be usedtherapeutically in the treatment of pathologies associated with I₁-receptors, especially in hypertension.

The absence of affinity for the α-receptors makes it possible to avoidthe undesirable central neuropharmacological effects usually encounteredin that type of treatment.

The invention relates to compounds of formula (I): ##STR3## wherein: R₁and R₂ are selected, each independently of the other, from hydrogen andan alkyl radical,

A is selected from the radicals: ##STR4## wherein: R₃ represents aradical selected from halogen, alkyl, alkoxy, amino, alkylamino,dialkylamino, carboxy, alkoxycarbonyl, 2-acetyl, trifluoromethyl andcyano,

R₄, R₅, R₆, R₇ and R₈ are selected, each independently of the others,from hydrogen, a halogen, an alkyl, alkoxy, amino, alkylamino,dialkylamino, carboxy, alkoxycarbonyl, cyano and a trifluoromethylradical,

R₉ represents the nitro radical,

with the proviso that A cannot represent a grouping selected from:dihalophenyl, trihalophenyl, 4-methylphenyl, 4-chlorophenyl,4-methoxyphenyl, 4-tert-butylphenyl and 3-(dimethylamino)phenyl,

optical isomers thereof in pure form or in the form of a mixture, andpharmaceutically acceptable addition salts thereof with an acid or base,

it being understood that: the terms "alkyl" and "alkoxy" representstraight-chained or branched radicals having from 1 to 6 carbon atoms.

The invention relates especially to the compounds of formula (I) whereinA represents the radical of formula (A₁) as defined in formula (I).

The invention relates especially to the compounds of formula (I) whereinA represents the radical of formula (A₂) as defined in formula (I).

The invention relates especially to the compounds of formula (I) whereinA represents the radical of formula (A₄): ##STR5## wherein R₃, R₄ and R₅are as defined in formula (I).

The invention relates more especially to the compounds of formula (I)wherein A represents the radical of formula (A₆): ##STR6## a particularcase of the radical (A₁) as defined in formula (I) wherein each of R₄and R₅ represents hydrogen.

The invention relates, for example, to the compounds of formula (I)wherein A represents a radical of formula A₆ and R₃ is selected fromhalogen, alkyl and alkoxy, especially alkyl.

Among the pharmaceutically acceptable acids that may be used to form anaddition salt with the compounds of the invention, the following acidsmay be mentioned, by way of non-limiting example: hydrochloric,sulphuric, phosphoric, tartaric, malic, maleic, fumaric, oxalic,methanesulphonic, ethanesulphonic, camphoric and citric acid.

Among the pharmaceutically acceptable bases that may be used to form anaddition salt with the compounds of the invention there may bementioned, by way of non-limiting example, sodium, potassium, calciumand aluminium hydroxides, alkali metal and alkaline earth metalcarbonates, and organic bases, such as triethylamine, benzylamine,diethanolamine, tert-butylamine, dicyclohexylamine and arginine.

More especially, alkyl radicals present in formula (I) are selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl and hexyl.

Alkoxy radicals present in formula (I) are selected from methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy and hexyloxy.

Halogens present in formula (I) are selected from bromine, chlorine,fluorine and iodine.

The invention relates also to a process for the preparation of thecompounds of formula (I), characterised in that a compound of formula(II): ##STR7## wherein A is as defined in formula (I) is reacted withsodium cyanamide to obtain a compound of formula (I/a): ##STR8## whereinA is as defined hereinbefore, which compound of formula (I/a) is thenmono- or di-alkylated at the primary amine to obtain a compound offormula (I/b) corresponding to a compound of formula (I) wherein R₁and/or R₂ represent alkyl, the compounds of formulae (I/a) and (I/b)forming the totality of the compounds of formula (I),

which compounds of formula (I) may, if desired, be

purified in accordance with one or more purification methods selectedfrom crystallisation, chromatography on silica gel, extraction,filtration and passing over carbon or resin,

separated, where appropriate, in pure form or in the form of a mixture,into their possible optical isomers using conventional separationtechniques,

or converted into pharmaceutically acceptable salts with an acid orbase.

The starting materials used in the process for the preparation of thecompounds of formula (I) are either commercial products or are readilyobtainable by a person skilled in the art.

For example, compounds of formula (I) are obtained in a customary mannerfrom phenol or the corresponding pyridinol and epichlorohydrin.

In order to obtain sodium cyanamide, sodium ethanolate is reacted withcyanamide in ethanol.

The compounds of formula (I) have very valuable pharmacologicalproperties from the point of view of the clinician and the doctor.

The compounds of the invention and the pharmaceutical compositionscomprising them are proving to be useful in the treatment of disordersassociated with I₁ -receptors.

In fact, I₁ -receptors are known to be the mediators of a hypotensiveaction of a central type, as has been demonstrated in studies on theeffects of rilmenidine.

I₁ -receptors are also known to be involved in stimulating the releaseof insulin by the β cells of the pancreas (Schulz et al.,Naunyn-Schmiedeberg's Arch. Pharmacol., (1989), 340 (6),712-714).

I₁ receptors are also implicated in anaemia, especially sickle cellanaemia, and in cancerous proliferation.

Now, the pharmacological study of compounds of the invention hasdemonstrated that they are not toxic and have a very strong selectiveaffinity for I₁ -receptors.

This allows it to be established that compounds of the invention areuseful in the treatment of cardiovascular pathologies and especiallyhypertension, in particular essential arterial hypertension, and also inthe treatment of diabetes, anaemia, especially sickle cell anaemia, andcancer.

The compounds will be used preferably in the treatment of essentialarterial hypertension.

The present invention relates also to pharmaceutical compositionscomprising the compounds of formula (I) or, where appropriate, apharmaceutically acceptable addition salt thereof with an acid or base,in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention, theremay be mentioned more especially those which are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration and especially tablets or dragees,sublingual tablets, sachets, packets, gelatin capules, glossettes,lozenges, suppositories, creams, ointments, dermal gels and drinkable orinjectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the mode of administration, the nature of the therapeutic indication andpossibly associated treatments, and ranges from 0.1 mg to 100 mg per 24hours in 1 or 2 doses, more especially from 1 to 10 mg, for example from1 to 2 mg.

The following Examples illustrate the invention but do not limit it inany way.

EXAMPLES 1 TO 25

The compounds of the following Examples are obtained by proceeding asdescribed in the general method of operation and using a suitablysubstituted epoxide:

General Method of Operation

The oxazoline heterocycle is formed by opening up the epoxide ring bythe action of sodium cyanamide. That reaction is carried out inmethanol, which has the advantage of rendering the medium homogeneousand especially of preventing hydrolysis of the sodium cyanamide. Yieldsare satisfactory.

0.2 mole of sodium cyanamide and 200 cm³ of anhydrous methanol areintroduced into a reactor. Once dissolution is complete, 0.2 mole ofepoxide is added dropwise; the temperature is advantageously maintainedbelow +20°. After twelve hours' stirring, 4,5-dihydro-oxazol-2-ylaminesometimes separates out in the solid state. It is purified by fractionalcrystallisation. When the reaction medium remains homogeneous, themethanol is removed by evaporation. The solid residue is a mixture of4,5-dihydro-oxazol-2-ylamine and sodium methanolate. Removal of thelatter by washing with water gives the same result as in the case above.##STR9##

EXAMPLE 1 5- (2-METHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

white crystalline powder Melting point (m.p.)=130° C. (heptane) pKa=8.54log P_(o/w) =1.69 dipole moment: benzene: 1.80 D dioxane: 2.07 D

IR (cm⁻¹) KBr disk: ν (NH): 3410; ν (C.tbd.N): 1680

¹ H NMR (CDCl₃) internal reference TMS, δ (ppm): 7.0 (m, 4H, arom); 4.91(m, 1H, CH--O); 4.88 (s, 2H, NH₂); 3.86 (m, 4H, CH₂); 2.3 (s, 3H, CH₃)

Elemental analysis: C₁₁ H₁₄ N₂ O₂ (M=206)

    ______________________________________                                                 % C         % H    % N                                               ______________________________________                                        Calculated:                                                                              64.08         6.80   13.59                                         Found:     64.09         6.84   13.52                                         ______________________________________                                    

Preparation: Epoxide: boiling point (b.p.): 88° C. (53.31 Pa) Yield: 49%Yield (oxazoline): 51%

EXAMPLE 2 5- (3-METHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE##STR10##

white crystalline powder m.p.=130° C. (C₂ HCl₃)

IR (cm⁻¹) KBr disk: ν (NH): 3420; ν (C.tbd.N): 1685

¹ H NMR (CDCl₃), internal reference TMS, δ (ppm): 7.00 (m, 4H, arom);4.90 (m, 1H, CH--O); 4.30 (s, 2H, NH₂); 3.82 (m, 4H, CH₂); 2.34 (s, 3H,CH₃)

Elemental analysis: C₁₁ H₁₄ N₂ O₂ (M=206)

    ______________________________________                                                 % C         % H    % N                                               ______________________________________                                        Calculated:                                                                              64.08         6.80   13.59                                         Found:     64.07         6.77   13.44                                         ______________________________________                                    

Preparation: Epoxide: b.p.: 100° C. (66.64 Pa) Yield: 72% Yield(oxazoline): 43%

EXAMPLE 3 5- (2-CHLOROPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₀ H₁₁ N₂ O₂ Cl (M=226.45) m.p.=142° C. (C₂ HCl₃) Yield: 21%

EXAMPLE 4 5- (3-CHLOROPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₀ H₁₁ N₂ O₂ Cl (M=226.45) m.p.=128° C. (CCl₄) Yield: 24%

EXAMPLE 5 5- (2-METHOXYPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₁ H₁₄ N₂ O₃ (M=222) m.p.=110° C. (C₂ HCl₃) Yield: 13%

EXAMPLE 6 5- (3-METHOXYPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₁ H₁₄ N₂ O₃ (M=222) m.p.=110° C. Yield: 28%

EXAMPLE 7 5- (2-ETHOXYPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₂ H₁₆ N₂ O₃ (M=236) m.p.=130° C. (CCl₄) Yield: 21%

EXAMPLE 8 5- (4-ETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₂ H₁₆ N₂ O₂ (M=220) m.p.=172° C. (C₂ H₅ OH) Yield: 45%

EXAMPLE 9 5- (2,6-DIMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₂ H₁₆ N₂ O₂ (M=220) m.p.=114° C. (heptane) Yield: 24%

EXAMPLE 10 5- (2,4-DIMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₂ H₁₆ N₂ O₂ (M=220) m.p.=116° C. (heptane) Yield: 31%

EXAMPLE 11 5- (3,4-DIMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₂ H₁₆ N₂ O₂ (M=220) m.p.=144° C. (C₂ HCl₃) Yield: 21%

EXAMPLE 12 5-{4-(1,1-DIMETHYLPROPYL)PHENOXY!METHYL}-4,5-DIHYDRO-OXAZOL-2-YLAMINE

C₁₅ H₂₂ N₂ O₂ (M=262) m.p.=104° C. (heptane) Yield: 11%

EXAMPLE 13 5- (2,3-DIMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=175° C. (C₂ H₅ OH)

EXAMPLE 14 5- (3-NITROPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINEEXAMPLE 15 5- (4-NITROPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINEEXAMPLE 16 5- (2,5-DIMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=131° C. (C₂ HCl₃)

EXAMPLE 17 5-(4-CHLORO-2-METHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=130° C. (C₂ Cl₄)

EXAMPLE 18 5- (2-ETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=109° C. (C₂ Cl₄)

EXAMPLE 19 5- (2-ISOPROPYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=134° C. (C₂ Cl₄)

EXAMPLE 20 5- (2-FLUOROPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=124° C. (CHCl₃)

EXAMPLE 21 5- (2-NITROPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=166° C. (toluene)

EXAMPLE 22 5- (2-CYANOPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=146° C. (toluene)

EXAMPLE 23 5- (2-ACETYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=142° C. (C₂ Cl₄)

EXAMPLE 24 5-(3-TRIFLUOROMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=10° C. (heptane)

EXAMPLE 25 5-(2,6-DIMETHOXYMETHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE

m.p.=180° C. (C₂ HCl₃)

EXAMPLE 26 N-n-PROPYL-N-5-(2-METHYLPHENOXY)METHYL-4,5-DIHYDRO-OXAZOL-2-YL!AMINE

In a reactor are introduced 0,01 mol of 5-(2-methylphenoxy)methyl!-4,5-dihydro-oxazol-2-ylamine and 100 ml ofacetone. Once dissolution is complete, 0,005 mol of 1-bromopropyl areadded and the whole is heated to ebullition during 48 hours. Afterfiltering off the formed solid and evaporating the solvent, the crudedesired product is purified by separation by column chromatography(eluent: chloroform/ammonia, 95:5).

C₁₄ H₂₀ N₂ O₂ M=248 White crystalline powder m.p.=108° C. (heptane)

EXAMPLE 27 N-ETHYL-N-5-(2-METHYLPHENOXY)METHYL-4,5-DIHYDRO-OXAZOL-2-YL!AMINE

By proceeding in a mammer analogous to that described in Example 26,replacing 1-bromopropyl by 1-bromoethyl, the title compound is obtained.

F=126° C. (heptane)

EXAMPLE 28 5- (2-METHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE(Isomer 1 of the compound of Example 1).

That isomer was obtained from the compound of Example 1 (racemic) byseparation by chromatography under the following conditions:

Column: CHIRALCEL OD Eluant: n-heptane/ethanol/diethylamine: 900/100/0.4Rate of flow: 1 ml/min. Injection: 4 μl of a solution of 4 mg/ml(dichloromethane/isopropanol mixture: 50/50) Detection: 220 nm.

EXAMPLE 29 5- (2-METHYLPHENOXY)METHYL!-4,5-DIHYDRO-OXAZOL-2-YLAMINE(Isomer 2 of the compound of Example 1)

Enantiomer of the compound described in Example 28, obtained accordingto the same process, starting from the compound of Example 1 (racemic).

PHARMACOLOGICAL STUDY EXAMPLE A: PROFILE OF BINDING TO IMIDAZOLINE I₁ -AND I₂ -RECEPTORS. (IN VITRO STUDY)

OBJECT:

To measure in vitro the binding affinity of the compounds of theinvention for I₁ - and I₂ -receptors, by determining the capacity ofthose compounds to displace specific radioligands of the imidazolineI₁ - and I₂ -receptors.

PROTOCOL:

The following Table gives the radioligand used to label the receptor,the compound and the concentration selected to determine thenon-specific fraction and the tissue selected.

    ______________________________________                                        Receptor or site                                                                       Radioligand non specific                                                                              Structure                                    ______________________________________                                        I.sub.1   3H!-clonidine +                                                                          10.sup.-5 M bovine lateral                                        10 μM of cold clonidine                                                                            reticular nucleus                                     norepinephrine                                                       I.sub.2   3H!-idazoxane +                                                                          10.sup.-5 M rabbit renal cortex                                   10 μM of idazoxane                                                         norepinephrine                                                       ______________________________________                                    

RESULTS:

The results obtained in vitro on the central or peripheral receptors andunder our experimental conditions demonstrate that the compounds of theinvention have a very strong affinity for the I₁ sites (see Table 1),whilst they bind with only very weak affinity to the I₂ -receptors ofrabbit renal cortex.

                  TABLE 1                                                         ______________________________________                                        Profile of binding to the I.sub.1 - and I.sub.2 -receptors                                 K.sub.i (M)                                                      EXAMPLE        I.sub.1  I.sub.2                                               ______________________________________                                        1              8.5 × 10.sup.-9                                                                  9.2 × 10.sup.-7                                 9              5.7 × 10.sup.-8                                                                  2.1 × 10.sup.-6                                 10             1.6 × 10.sup.-7                                                                  3.9 × 10.sup.-6                                 13             6.4 × 10.sup.-8                                                                  4.5 × 10.sup.-7                                 16             8.5 × 10.sup.-8                                                                  1.6 × 10.sup.-6                                 17             1.2 × 10.sup.-7                                                                  1.0 × 10.sup.-6                                 18             1.0 × 10.sup.-7                                                                  1.8 × 10.sup.-6                                 19             1.2 × 10.sup.-7                                                                  2.1 × 10.sup.-6                                 20             2.1 × 10.sup.-7                                                                  1.3 × 10.sup.-6                                 21             5.0 × 10.sup.-7                                                                  3.9 × 10.sup.-6                                 22             4.8 × 10.sup.-8                                                                  2.4 × 10.sup.-6                                 23             1.7 × 10.sup.-7                                                                  7.7 × 10.sup.-6                                 26             6.7 × 10.sup.-7                                                                  1.4 × 10.sup.-6                                 27             1.7 × 10.sup.-7                                                                  1.0 × 10.sup.-6                                 28             3.7 × 10.sup.-7                                                                  1.3 × 10.sup.-5                                 29             5.8 × 10.sup.-9                                                                  7.5 × 10.sup.-6                                 ______________________________________                                    

EXAMPLE B: PROFILE OF BINDING TO THE CENTRAL ALPHA 1- AND ALPHA2-ADRENORECEPTORS. (IN VITRO STUDY)

OBJECT:

To measure in vitro the binding affinity of the compounds of theinvention for the central alpha 1- (α₁ -) and alpha 2- (α₂ -) receptorsby determining the capacity of the compound in question to displacespecific radioligands of those receptors.

RESULTS:

The results obtained in vitro on the adrenoreceptors under ourexperimental conditions demonstrate that the compounds of the inventionhave only very weak affinity for the alpha 1-adrenoreceptors (K_(i) >7μM) and for the alpha 2-adrenoreceptors (K_(i) >10 μM).

PROTOCOL:

The following Table gives the radioligand used to label the receptor,the compound and the concentration selected to determine thenon-specific fraction and the tissue selected.

    ______________________________________                                        Receptor or site                                                                        Radioligand                                                                              non specific                                                                              Structure                                    ______________________________________                                        Alpha 1    3H!-prazosin                                                                            10.sup.-5 M calf frontal cortex                                               phentolamine                                             Alpha 2    3H!-RX    10.sup.-5 M calf frontal cortex                                    821002     yohimbine                                                ______________________________________                                    

EXAMPLE C: PHARMACEUTICAL COMPOSITION: TABLETS

Tablets each containing 1 mg of 5-(2-methylphenoxy)methyl!-4,5-dihydro-oxazol-2-ylamine

    ______________________________________                                        5- (2-methylphenoxy)methyl!-4,5-dihydro-oxazol-2-ylamine                                                   1 g                                              Wheat starch                 20 g                                             Corn starch                  20 g                                             Lactose                      30 g                                             Magnesium stearate           2 g                                              Silica                       1 g                                              Hydroxypropy cellulose       2 g                                              ______________________________________                                    

We claim:
 1. A compound selected from those of formula (I): ##STR11##wherein: R₁ and R₂ are selected, each independently of the other, fromhydrogen and alkyl,A is selected from the radicals: ##STR12## wherein:R₃ represents a radical selected from halogen, alkyl, alkoxy, amino,alkylamino, dialkylamino, carboxy, alkoxycarbonyl, 2-acetyl,trifluoromethyl, and cyano, R₄, R₅, R₆, R₇ and R₈ are selected, eachindependently of the others, from hydrogen, halogen, alkyl, alkoxy,amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, cyano, andtrifluoromethyl, R₉ represents nitro,with the proviso that A cannotrepresent a grouping selected from: dihalophenyl, trihalophenyl,4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-tert-butylphenyl, and3-(dimethylamino)phenyl, optical isomers thereof, andpharmaceutically-acceptable addition salts thereof with an acid or base,it being understood that: the terms "alkyl" and "alkoxy" representstraight-chained or branched radicals having 1 to 6 carbon atomsinclusive.
 2. A compound selected from those of formula (I), wherein Arepresents the radical of formula (A₄): ##STR13## wherein R₃, R₄ and R₅are as defined in formula (I).
 3. A compound selected from those offormula (I) according to claim 1, wherein A represents the radical offormula (A₆): ##STR14## wherein R₃ is as defined in claim
 1. 4. Acompound according to claim 1 which is 5-(2-methylphenoxy)methyl!-4,5-dihydro-oxazol-2-ylamine.
 5. A compoundaccording to claim 1 which is (5R*)-5-(2-methylphenoxy)methyl!-4,5-dihydro-oxazol-2-ylamine.
 6. A compoundaccording to claim 1 which is 5-(2,5-dimethylphenoxy)methyl!-4,5-dihydro-oxazol-2-ylamine.
 7. A compoundaccording to claim 1 which is 5-2,6-(dimethyl)phenoxymethyl!-2-amino-2-oxazoline.
 8. A compoundaccording to claim 1 which is N-n-propyl-N-5-(2-methylphenoxy)methyl-4,5-dihydro-oxazol-2-yl!amine.
 9. A compoundaccording to claim 1 which is N-ethyl-N-5-(2-methylphenoxy)methyl-4,5-dihydro-oxazol-2-yl!amine.
 10. A methodfor treating a mammal afflicted with a disease requiring a selective I₁-receptor ligand comprising the step of administering to said mammal anamount of a compound of claim 1 which is effective for alleviation ofsaid disease.
 11. A pharmaceutical composition useful as a selective I₁-receptor ligand comprising an amount of a compound as claimed in claim1 which is effective as a selective I₁ -receptor ligand, together with apharmaceutically-acceptable excipient.
 12. A method of claim 10 whereinthe compound is in the form of a pharmaceutical composition togetherwith a pharmaceutically acceptable excipient.